| Title: | Single-cell chromatin accessibility identifies pancreatic islet cell type- and state-specific regulatory programs of diabetes risk |
| Journal: | Nature Genetics |
| Published: | 1 Apr 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33795864/ |
| DOI: | https://doi.org/10.1038/s41588-021-00823-0 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037575 |
Publication 9623
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Abstract
Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.</p>
20 Authors
- Joshua Chiou
- Chun Zeng
- Zhang Cheng
- Jee Yun Han
- Michael Schlichting
- Michael Miller
- Robert Mendez
- Serina Huang
- Jinzhao Wang
- Yinghui Sui
- Allison Deogaygay
- Mei-Lin Okino
- Yunjiang Qiu
- Ying Sun
- Parul Kudtarkar
- Rongxin Fang
- Sebastian Preissl
- Maike Sander
- David U. Gorkin
- Kyle J. Gaulton
1 Application
| Application ID | Title |
|---|---|
| 24058 | Genomic mechanisms of genetic variants influencing risk of diabetes and diabetic complications |
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